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PubMed1999

Maturation-dependent durability of spontaneous cartilage repair in rabbit knee joint.

The spontaneous healing of osteochondral defects in the knee joints of immature rabbits within the first 12 weeks after surgery showed a faster filling and earlier tissue specialization than in adult animals. The purpose of the present study was to investigate whether the better short-term quality of spontaneous repairs in immature animals lasted over a period of 48 weeks. A full-thickness osteochondral defect was created on the medial femoral condyle in both knees of 10 young, 10 adolescent, and 10 adult rabbits. Equal numbers of animals were evaluated after 24 and 48 weeks. At both time intervals, bonding to adjacent cartilage and proteoglycan content of the matrix were better in the repairs of young than in adult animals. Repairs in the former had cellularity similar to the adjacent cartilage and were composed of 90% hyaline-like cartilage, which did not decrease with time. In contrast, repairs in older animals formed less hyaline-like cartilage and had a lower cellularity than the adjacent cartilage. However, the surface of the repaired tissue was similarly disrupted in all age groups, and the mechanical properties remained inferior to adjacent or normal cartilage. Repairs in older animals showed signs of degeneration with time. The initial better repair quality in a young, growing animal remained up to 48 weeks when the animal had already reached maturity, indicating that successful initial promotion of cartilage repair may even lead to better results in the long term. However, it has to be pointed out that the morphologically good repairs with hyaline-like cartilage appearance, normal cellularity, and durability of up to 48 weeks were unable to reestablish and maintain a cartilage-like mechanical function.

Age Factors↗
PubMed1999

A novel approach to observing articular cartilage deformation in vitro via magnetic resonance imaging.

The design of a pressure cell that compresses a cartilage specimen in one dimension within an imaging magnet is presented. One-dimensional projection images in a direction perpendicular to the articular surface of the cartilage specimen were used to generate a uniaxial confined deformation creep curve for normal and trypsin-degraded cartilage specimens during a continuous 0.690 MPa (100 psi) pressure application. The resulting curves are shown to fit a two time constant viscoelastic model well and also indicate that the elastic modulus of cartilage decreases and the deformation rate increases upon trypsin proteolysis. Furthermore, cartilage permeability is shown as a function of cartilage strain for both the normal and trypsin-degraded case. Several two-dimensional slice-selective images were collected both before and after 80 minutes of continuous compression. These images were used to evaluate the relative changes in the spin-lattice, T1, and spin-spin, T2, relaxation time constant maps for both normal and degraded cartilage specimens in response to compression. The results of this study demonstrate the utility of a novel, non-magnetic, cartilage compression device and also support the validity of a simple two-component rheological model of articular cartilage.

Animals↗
PubMed1999

Relationship of matrix metalloproteinases and their inhibitors to cartilage proteoglycan and collagen turnover: analyses of synovial fluid from patients with osteoarthritis.

OBJECTIVE: To determine the relationship between matrix metalloproteinases (MMPs), their inhibitors, and the turnover of matrix molecules in articular cartilage from patients with osteoarthritis (OA). METHODS: Synovial fluid samples were collected from the knees of 54 patients with OA. Radiographic evaluations and magnetic resonance imaging were performed on the knees of 34 OA patients to classify the stage of the disease. Biochemical analyses and immunoassays were used to measure the concentrations of MMP-1, MMP-3, tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, the disaccharide of hyaluronic acid, the proteoglycan glycosaminoglycan disaccharides of chondroitin 4-sulfate (delta di-CS4) and chondroitin 6-sulfate (delta di-CS6), the 846 epitope on chondroitin sulfate of cartilage proteoglycan aggrecan (putative biosynthetic marker), the keratan sulfate (KS) epitope of aggrecan (putative degradation marker), and the C-propeptide of cartilage type II procollagen (CPII) (biosynthetic marker). RESULTS: The concentration of TIMP-1 was directly correlated with the levels of MMP-1 and MMP-3 (both were also correlated with each other), confirming earlier results. There was an inverse correlation between the delta di-CS6:delta di-CS4 ratio and the concentration of MMP-3. The level of delta di-CS6 was correlated with that of the KS epitope, and to a lesser degree, with that of the 846 epitope (the latter was also correlated with the level of delta di-CS4). The concentration of TIMP-1 correlated with that of the 846 epitope, whereas TIMP-2 levels correlated with those of CPII. There were significantly lower concentrations of delta di-CS6, delta di-CS4, the 846 epitope, and CPII in synovial fluid from patients with late-stage OA. CONCLUSION: These observations suggest a link between proteolysis and inhibitor concentrations in OA cartilage. Production of TIMPs appears to be individually linked to the synthesis of specific cartilage molecules. The reduction in the amount of cartilage-matrix structural components suggests that there is a measurable loss of cartilage in the late stages of the disease, as suggested previously. The resultant composition of the cartilage suggests that the loss may primarily involve "resident" molecules originally present in healthy cartilage.

Aged↗
PubMed2000

Differences in type II collagen degradation between peripheral and central cartilage of rat stifle joints after cranial cruciate ligament transection.

OBJECTIVE: Type II collagen degradation is thought to be the key process in cartilage degradation during the development of osteoarthritis (OA). In this study, we investigated the kinetics of type II collagen degradation during surgically induced OA. METHODS: Experimental OA was induced in male Wistar rats by transecting the cranial (anterior) cruciate ligament (CCL). Hematoxylin and eosin staining was used to study overall cartilage degradation, while immunostained sections were used to demonstrate denatured type II collagen (Col2-3/4m antibody) and the collagenase cleavage site in type II collagen (Col2-3/ 4Cshort antibody). RESULTS: During the first 3-4 weeks, cartilage destruction, associated with chondrocyte death, proteoglycan depletion, and a marked increase in the collagenase cleavage neoepitope, was mainly located at the margins of the cartilage. From weeks 3-4, the central part of the cartilage showed increased surface fibrillation and apparent chondrocyte death. In these areas, increased denatured type II collagen staining but little cleavage-site staining was present. CONCLUSION: These results indicate that cartilage degradation after CCL transection in the rat consists of 2 phases. An early phase located at the cartilage margins and a late phase located at the central part of the cartilage. In the early phase, collagenase-dependent cartilage damage occurred. During the late phase, the level of type II collagen denaturation increased.

Animals↗
PubMed2000

The increased swelling and instantaneous deformation of osteoarthritic cartilage is highly correlated with collagen degradation.

OBJECTIVE: To provide evidence for the hypothesis that the loss of tensile strength of osteoarthritic (OA) cartilage (resulting in swelling-the hallmark of OA) is due to an impaired collagen network and not to loss or degradation of proteoglycans. METHODS: The amount of degraded collagen molecules, the fixed charge density (FCD) on a dry-weight basis, the degree of swelling in saline, and the instantaneous deformation (ID; a test reflecting the tensile stiffness of the collagen network) were measured in full-depth OA femoral condyle samples. In addition, levels of the crosslink hydroxylysylpyridinoline (HP), the amount of degraded collagen molecules, and the degree of swelling were determined in the 3 zones (surface, middle, and deep) of OA cartilage. We also compared the ID of normal and OA cartilage. RESULTS: In full-depth OA cartilage, a close relationship was found between swelling and ID. Swelling and ID correlated strongly with the amount of degraded collagen molecules, and were not related to FCD. OA cartilage showed the same zonal pattern in HP levels as normal cartilage (i.e., an increase with depth). No relationship was found between collagen crosslinking and swelling of the surface, middle, and deep zones. In all 3 zones, swelling was proportional to the amount of degraded collagen molecules. Compared with that of normal cartilage, the change in ID of OA cartilage was most pronounced at the surface in a direction parallel to the direction of the collagen fibrils. CONCLUSION: The decreased stiffness of the OA collagen network (as measured by swelling and ID) is strongly related to the amount of degraded collagen molecules. The anisotropy in ID parallel and perpendicular to the direction of the fibrils revealed that the impairment of strength resides mainly in, and not between, the fibrils. Proteoglycans play only a minor role in the degeneration of the tensile stiffness of OA cartilage.

Aged↗
PubMed2000

Sex and site differences in cartilage development: a possible explanation for variations in knee osteoarthritis in later life.

OBJECTIVE: To test the hypothesis that sex-related and joint compartment-related differences in the risk of osteoarthritis (OA) of the knee might be associated with variations in cartilage development, we investigated knee cartilage volume in healthy children. METHODS: We studied 92 children who were randomly selected from among students in grades 3-12 of a single school in Hobart, Tasmania (49 boys, 43 girls; age range 9-18 years). Articular cartilage thickness and volume were determined at the patella, medial tibial compartment, and lateral tibial compartment by magnetic resonance imaging (MRI). Sagittal T1-weighted fat-suppressed MRI images were obtained and processed on an independent computer work station. RESULTS: Males had significantly more knee cartilage than females. Sex accounted for 6-36% of the variation in cartilage thickness and volume, which was statistically significant at all sites. Even after adjustment for age, body mass index, bone area, and physical activity, males had 16-31% higher cartilage volume; this was most marked at the medial tibial site. In addition, lateral tibial thickness was greater than medial tibial thickness (5.9 versus 3.6 mm; P < 0.0001) and lateral tibial volume was greater than medial tibial volume (2,823 versus 2,299 microl; P < 0.0001). Furthermore, physical activity was a significant explanatory factor for cartilage volume at all sites (R2 7-14% depending on site; all P < 0.05). The most consistent activity association was with vigorous activity in the previous 2 weeks (difference between any vigorous activity versus none 22-25% greater; all P < 0.05). CONCLUSION: Sex- and joint compartment-related differences in cartilage development may be one explanation for variations in the pattern of knee OA seen in later life. Furthermore, the physical activity associations suggest that cartilage development is amenable to modification.

Adolescent↗
PubMed2001

Alternative messenger RNA splicing and enzyme forms of cathepsin B in human osteoarthritic cartilage and cultured chondrocytes.

OBJECTIVE: In previous studies, we suggested that cathepsin B, which is present at sites of cartilage remodeling in osteoarthritis (OA), may act as an antagonist of cartilage repair, an enhancer of the action of metalloproteinases, and a mediator of cartilage neovascularization and mineralization. Alternative splicing of cathepsin B pre-messenger RNA (pre-mRNA) and/or mRNA overexpression is a plausible regulatory mechanism. In the present study, we investigated the abundance of cathepsin B transcripts and the properties of cathepsin B protein in normal and OA cartilage, osteophytes, and cultured chondrocytes. METHODS: Cathepsin B mRNA splice variants containing the full-length transcript (CB) and the variants lacking either exon 2 (CB[-2]) or lacking exons 2 and 3 (CB[-2,3]) were measured by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot assays and were localized by in situ RT-PCR. Cathepsin B protein was analyzed by electrophoretic, Western blot, and chromatographic methods. RESULTS: The relative content of CB, CB(-2), and CB(-2,3) varied considerably in OA cartilage and osteophytes, with less variation in normal cartilage. The mean cathepsin B mRNA level was significantly higher in OA cartilage and osteophytes than in normal cartilage. Normal cultured chondrocytes attained cathepsin B mRNA levels similar to those in OA cartilage. Enzyme overexpression resulted in the secretion of procathepsin B, followed by activation to the proteolytically active form. CONCLUSION: The high levels of CB and CB(-2) are consistent with an overproduction of secreted procathepsin B in OA. Up-regulation of chondrocyte cathepsin B, which takes place at both the transcriptional and the translational level, suggests a leading role of the enzyme in the progression of OA.

Aged↗
PubMed1992

The influence of bone and marrow on cartilage hypertrophy and degradation during 30-day serum-free culture of the embryonic chick tibia.

In this study, an organ culture system is defined which demonstrates complete loss of cartilage matrix from embryonic chick tibiae. Efficient loss of the cartilage matrix occurs within 30 days of serum-free culture only when the intact tibiae containing bone, marrow, and cartilage tissue are cultured. During organ culture nonhypertrophic chondrocytes become hypertrophic and stain positively for type X collagen and alkaline phosphatase. The cartilage loses Safranin O staining, and finally all cartilage matrix disappears leaving the bony collar and marrow cells. If the tibial cartilage is separated from the bony collar and cultured alone in serum-free medium, the nonhypertrophic chondrocytes also hypertrophy; the matrix loses Safranin O staining; however, some components of the matrix including type X collagen still remain after 30 days. In the presence of serum, the chondrocytes will hypertrophy but cartilage degradation is not evident. The results of this study support the conclusions that 1) hypertrophy is inherently programmed in the chondrocyte and 2) while Safranin O staining of cartilage cultured alone is diminished in serum-free organ culture, the degradation of cartilage is complete only when bone and marrow are also present.

Alkaline Phosphatase↗
PubMed1989

Suppression of glycosaminoglycan synthesis by articular cartilage, but not of hyaluronic acid synthesis by synovium, after exposure to radiation.

We recently found that injection of 2 mCi of yttrium 90 (90Y; approximately 23,000 rads) into normal canine knees stimulated glycosaminoglycan (GAG) synthesis by femoral condylar cartilage. The present investigation was conducted to determine whether radiation affects cartilage metabolism directly. Rates of GAG synthesis and degradation in normal canine articular cartilage were studied following irradiation. Cultured synovium from the same knees was treated similarly, to determine the effects of irradiation on hyaluronic acid synthesis. Twenty-four hours after exposure to 1,000 rads, 10,000 rads, or 50,000 rads, 35S-GAG synthesis by the cartilage was 93%, 69%, and 37%, respectively, of that in control, nonirradiated cartilage. The effect was not rapidly reversible: 120 hours after exposure to 50,000 rads, GAG synthesis remained at only 28% of the control level. Autoradiography showed marked suppression of 35S uptake by chondrocytes after irradiation. Cartilage GAG degradation was also increased following irradiation: 4 hours and 8 hours after exposure to 50,000 rads, the cartilage GAG concentration was only 66% and 54%, respectively, of that at time 0, while corresponding values for control, nonirradiated cartilage were 90% and 87%. In contrast to its effects on cartilage GAG metabolism, radiation at these levels had no effect on synovial hyaluronic acid synthesis.

Animals↗
PubMed1988

Response of the intermaxillary suture cartilage to alterations in masticatory function.

Like the condylar cartilage of the mandible, the cartilage at the intermaxillary suture in the rat is secondary in origin and persists well into adulthood. While the condylar cartilage is generally considered to be responsive to changes in its local biomechanical environment, little is known of the response of the intermaxillary suture cartilage to similar stimuli. In order to study the effect of changes in occlusal loads on intermaxillary suture cartilage metabolism, male weanling Sprague-Dawley rats were divided into four groups: soft diet (to discourage molar mastication), incisor clipped (to discourage incision), incisor clipped/soft diet (both treatments), and control (untreated). At 39 days of age, the intermaxillary suture opposite the first molars was removed and compared to control tissue by using histological, histochemical, and biochemical analyses. Alcian blue-stained coronal sections demonstrated moderate decreases in staining intensity and decreased chondrocyte hypertrophy in the soft diet and incisor-clipped groups. However, sutures in the incisor-clipped/soft diet group showed a considerably reduced extent of cartilage and greatly diminished cartilage hypertrophy. [35S]-sulfate incorporation (dpm/micrograms DNA) into acid-insoluble proteoglycans was significantly reduced (P less than or equal to .01) in all three experimental groups compared to controls. [35S] incorporation was further reduced in the incisor-clipped/soft diet group relative to both of the other experimental groups. Staining for alkaline phosphatase activity showed decreased intensity in the experimental groups and was almost absent in the incisor-clipped/soft diet group. These data demonstrate the plasticity of the intermaxillary suture cartilage and provide circumstantial evidence that the observed changes in cartilage morphology and metabolism may be attributable to alterations in the local biomechanical environment of the suture.

Alkaline Phosphatase↗
PubMed2002

Acidic cysteine endoproteinase cathepsin K in the degeneration of the superficial articular hyaline cartilage in osteoarthritis.

OBJECTIVE: To measure cartilage pH in patients with osteoarthritis (OA) and to analyze the presence of cathepsin K, the recently discovered acidic endoproteinase, in phenotypically altered chondrocytes. METHODS: Intraoperative measurements of the pH of clinically normal, fibrillated, superficially fissured, and deeply fissured cartilage surfaces (grades 0-3, respectively) in OA patients undergoing primary hip replacement surgery were performed with the use of a sting electrode sterilized with microbicidic plasma. Fluorescent pH probes were used for in situ assessment of cartilage matrix pH. Cathepsin K was assessed using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry methods. RESULTS: The pH of grade 0 cartilage surfaces was 7.1 +/- 0.4 (mean +/- SD), compared with 6.2 +/- 0.9 (P < 0.05), 5.7 +/- 1.0 (P < 0.001), and 5.5 +/- 1.0 (P < 0.001) for grades 1-3 cartilage surfaces, respectively. Fluorescent pH probes and acid-dependent autocatalytic conversion of cathepsin K into its active, low molecular weight form in cartilage confirmed these findings. Cathepsin K messenger RNA levels increased in relation to the severity of OA, and the number of cathepsin K-containing chondrocytes increased from a mean +/- SD of 12 +/- 3 in grade 0 cartilage surfaces to 47 +/- 7, 50 +/- 6, and 100 +/- 12 in grades 1-3 cartilage surfaces, respectively (P < 0.001 for all comparisons). CONCLUSION: Acid-activated, but pharmacologically inhibitable, cathepsin K is induced in phenotypically altered chondrocytes in OA. The findings suggest that cathepsin K, rather than neutral matrix metalloproteinases, degrades the superficial gliding surfaces of the articular hyaline cartilage in OA.

Acids↗
PubMed2002

The insulin-like growth factor binding proteins in uncultured human cartilage: increases in insulin-like growth factor binding protein 3 during osteoarthritis.

OBJECTIVE: To assess changes in the insulin-like growth factor binding proteins (IGFBPs) in uncultured cartilage during stages of osteoarthritis (OA), and to determine if OA cartilage is capable of autocrine secretion of IGFBPs. METHODS: Articular cartilage was dissected from fibrillated and nonfibrillated sites of 11 human femoral heads, and extracted in buffer containing 8M urea. IGFBPs were identified by immunoprecipitation and subsequent analysis by (125)I-IGF-2 Western ligand blotting (WLB), radioimmunoassay, or 2-site immunoradiometric assay (IRMA). IGFBPs were assessed in cartilage extracts by WLB. IGFBP-3 content was determined by IRMA and synthesis by metabolic labeling with (35)S-cysteine in organ cultures. RESULTS: Sample grouping into 3 distinct OA strata was supported by gross pathology of the femoral heads, histologic grading of cartilage slices, and biochemical analysis of the glycosaminoglycan and protein content of the extracts. Group I was normal/mild OA, group II was intermediate OA, and group III was severe OA. IGFBP-2 was present in all samples, IGFBP-4 in sporadic samples, and BP-3 in group II-III samples. By IRMA, group I had a mean +/- SD of 6.26 +/- 2.6 ng IGFBP-3/mg soluble protein (IGFBP-3) (n = 6), group II had a mean +/- SD 14 +/- 7.5 IGFBP-3 (n = 10), and group III had a mean +/- SD 17.03 +/- 8.94 IGFBP-3 (n = 6). Analysis of variance showed group differences (F[3,19] = 3.84, P = 0.04), and post hoc tests revealed that IGFBP-3 levels were higher for group III versus group I (P = 0.04). OA cartilage synthesized IGFBP-3. CONCLUSION: Increases in net cartilage content of IGFBP-3 occurred in intact OA cartilage, reaching statistically significant elevation in severe disease. There was autocrine IGFBP-3 production in OA cartilage.

Autocrine Communication↗
PubMed2002

Detection of nitrotyrosine in aging and osteoarthritic cartilage: Correlation of oxidative damage with the presence of interleukin-1beta and with chondrocyte resistance to insulin-like growth factor 1.

OBJECTIVE: To determine whether oxidative damage to cartilage proteins can be detected in aging and osteoarthritic (OA) cartilage, and to correlate the results with the local production of interleukin-1beta (IL-1beta) and the responsiveness of isolated chondrocytes to stimulation with insulin-like growth factor 1 (IGF-1). METHODS: The presence of nitrotyrosine was used as a measure of oxidative damage. Histologic sections of knee articular cartilage, obtained from young adult and old adult cynomolgus monkeys, which develop age-related, naturally occurring OA, were evaluated. Each cartilage section was graded histologically on a scale of 0-7 for the presence of OA-like changes, and serial sections were immunostained using antibodies to nitrotyrosine and IL-1beta. Chondrocytes isolated and cultured from cartilage adjacent to the sections used for immunostaining were tested for their response to IGF-1 stimulation by measuring sulfate incorporation in alginate cultures. For comparison with the monkey tissues, cartilage sections from human tissue donors and from tissue removed at the time of OA-related joint replacement surgery were also immunostained for nitrotyrosine and IL-1beta. RESULTS: The presence of nitrotyrosine was associated with aging and with the development of OA in cartilage samples from both monkeys and humans. All sections that were highly positive for IL-1beta also showed staining for nitrotyrosine. However, in a few sections from older adult monkeys and humans, nitrotyrosine was present but IL-1beta was absent, suggesting that some age-related oxidative damage is independent of IL-1beta. In chondrocytes that were isolated from monkey cartilage positive for nitrotyrosine or IL-1beta, the response to stimulation with IGF-1 was significantly reduced. In some samples from older adult monkeys, IGF-1 resistance was seen in cells isolated from tissue that did not stain for nitrotyrosine or IL-1beta. CONCLUSION: Oxidative damage due to the concomitant overproduction of nitric oxide and other reactive oxygen species is present in both aging and OA cartilage. This damage can contribute to the resistance of chondrocytes to IGF-1 stimulation, but it is unlikely to be the sole cause of IGF-1 resistance in these chondrocytes.

Aging↗
PubMed2002

Cartilage-specific constitutive expression of TSG-6 protein (product of tumor necrosis factor alpha-stimulated gene 6) provides a chondroprotective, but not antiinflammatory, effect in antigen-induced arthritis.

OBJECTIVE: To study the chondroprotective effect of constitutively expressed TSG-6 protein (tumor necrosis factor alpha-induced protein 6; Tnfip6) in cartilage, using antigen-induced arthritis (AIA) in mice. METHODS: Transgenic mice constitutively expressing TSG-6 protein in cartilage were generated. Cartilage-specific constitutive expression of TSG-6 protein was confirmed by in situ hybridization, Western blot analysis, and immunohistochemistry. Control and transgenic mice were immunized with methylated bovine serum albumin (mBSA), and arthritis was induced by the intraarticular injection of mBSA. Mice were monitored up to day 35 after the challenge, and knee joint sections were examined for loss of cartilage proteoglycan (aggrecan) using Safranin O staining and antibodies to neoepitopes generated by various metalloproteinases (MPs). The loss of aggrecan in Safranin O-stained sections was quantified by morphometric methods. RESULTS: Tsg6/tnfip6 transgenic mice constitutively expressed tsg6/tnfip6 messenger RNA and corresponding TSG-6 protein in cartilage from embryonic life through adulthood, without any phenotypic abnormalities. These mice were used for AIA studies. Intraarticular injection of mBSA uniformly induced severe inflammation both in control (wild-type and an irrelevant transgenic line) mice and in tsg6/tnfip6 transgenic mice. In contrast to the mBSA-injected knee joints of control animals that were heavily damaged from day 5, the cartilage of transgenic mice that constitutively expressed TSG-6 protein remained intact for at least 1 week, and this was followed by a relatively reduced loss of aggrecan. Concomitant with the loss of aggrecan, MP-generated neoepitopes accumulated in unprotected joints. By day 35, the proteoglycan content returned to nearly normal levels in tsg6/tnfip6 transgenic mice, whereas it remained low in MP-damaged knee cartilage of control mice. CONCLUSION: TSG-6 protein is known to form a complex with inter-alpha-inhibitor (IalphaI), a potent serine protease inhibitor, which may be immobilized via the hyaluronan (HA)-binding domain of TSG-6 protein in the HA-rich extracellular matrix of cartilage. Thus, the local accumulation of TSG-6 protein and TSG-6 protein-bound IalphaI in tsg6/tnfip6 transgenic mice may inhibit serine proteases and subsequent activation of MPs. It is suggested that this mechanism might protect cartilage from extensive degradation even in the presence of acute inflammation.

Animals↗
PubMed2002

Induction of advanced glycation end products and alterations of the tensile properties of articular cartilage.

OBJECTIVE: To determine whether increasing advanced glycation end products (AGEs) in bovine articular cartilage to levels present in aged human cartilage modulates the tensile biomechanical properties of the tissue. METHODS: Adult bovine articular cartilage samples were incubated in a buffer solution with ribose to induce the formation of AGEs or in a control solution. Portions of cartilage samples were assayed for biochemical indices of AGEs and tested to assess their tensile biomechanical properties, including stiffness, strength, and elongation at failure. RESULTS: Ribose treatment of cartilage induced increases in tissue fluorescence, absorbance, and pentosidine content (P < 0.001 for each comparison) by amounts similar to those that occur during aging in humans. Ribose treatment of cartilage also induced an increase in dynamic modulus (60% increase) and strength (35% increase), and a decrease (25% decrease) in strain (P < 0.001 for each comparison). CONCLUSION: The concomitant increase in AGEs and alteration of tensile properties of cartilage after ribose treatment suggest that aging-associated changes in AGEs have functional consequences for this tissue. The AGE-associated increases in strength and stiffness of cartilage may be beneficial by counteracting the decreases in these properties that are associated with degeneration. Conversely, the AGE-associated decrease in failure length, or increase in brittleness, together with increased stiffness may predispose cartilage to increased stress concentration, fracture, and aging-associated biomechanical dysfunction.

Animals↗
PubMed2003

Feasibility of T and Z scores from magnetic resonance imaging data for quantification of cartilage loss in osteoarthritis.

OBJECTIVE: T scores (an indicator of the difference between patients and young healthy subjects) and Z scores (an indicator of the difference between patients and age-matched healthy subjects) are used in the diagnosis of osteoporosis and form the current basis for the definition of osteoporosis by the World Health Organization. We tested the feasibility of using T and Z scores derived from quantitative cartilage imaging with magnetic resonance imaging (MRI) for the diagnosis of osteoarthritis (OA). METHODS: High-resolution MR images of tibial cartilage were acquired from 126 young healthy adults (ages 20-35 years), 24 age-matched elderly healthy adults (ages 50-75 years), 7 OA patients prior to tibial osteotomy, and 7 OA patients prior to knee arthroplasty. Cartilage volume, thickness, surface area, and original joint surface area (before onset of disease) were determined in the medial and lateral tibia. RESULTS: The cartilage volume of the medial tibia of osteotomy patients with varus malalignment displayed moderate T scores (-1.0), and more negative T scores (-3.8) were observed in knee arthroplasty patients with varus malalignment. Normalization of the cartilage volume to the original joint surface area substantially enhanced the scores in patients undergoing osteotomy (-2.3) and in patients undergoing knee arthroplasty (-5.5), and this was superior to the normalization ratios of cartilage volume to body height and cartilage volume to body weight, in terms of distinguishing the loss of articular cartilage. CONCLUSION: Quantitative analysis of OA by MRI is feasible using T and Z scores. However, cartilage volume should be normalized to the individual joint surface area in order to maximize the discriminatory power of this technique for the diagnosis of OA.

Adult↗
PubMed2004

Influence of tissue maturation and antioxidants on the apoptotic response of articular cartilage after injurious compression.

OBJECTIVE: To study the influence of tissue maturation and antioxidants on apoptosis in bovine articular cartilage induced by injurious compression. METHODS: Bovine articular cartilage disks were obtained from the femoropatellar groove of animals ages 0.5-23 months and placed in culture. Cartilage disks were preincubated overnight with the cell-permeable superoxide dismutase (SOD) mimetic Mn(III) porphyrin (0-12.5 microM) or alpha-tocopherol (0-50 microM) and then injured by a single unconfined compression to a final strain of 50% at a velocity of 1 mm/second. After 4 days of additional incubation, the disks were fixed and embedded for light and electron microscopy. Apoptotic cells were quantified morphologically by the appearance of nuclear blebbing on light microscopy. Biosynthetic activity was demonstrated by incorporation of radiolabeled proline. The antioxidative action of the SOD mimetic was confirmed by histologic examination of cartilage after incubation with nitroblue tetrazolium. RESULTS: Injurious compression induced significantly more apoptosis in cartilage disks from newborn calves (22% of cells) than in cartilage from more mature cows (2-6%). In cartilage from 22-month-old animals, the SOD mimetic reduced the percentage of apoptotic cells induced by injury in a dose-dependent manner (complete inhibition with 2.5 microM), while alpha-tocopherol had no effect. Neither antioxidant altered protein biosynthesis or cellular ultrastructure. CONCLUSION: Our data suggest that the apoptotic response of articular cartilage to mechanical injury is affected by maturation and is mediated in part by reactive oxygen species. The antioxidative status of the tissue might be important for the prevention of mechanically induced cell death in articular cartilage.

Age Factors↗
PubMed2004

Failure of in vitro-differentiated mesenchymal stem cells from the synovial membrane to form ectopic stable cartilage in vivo.

OBJECTIVE: We previously reported the identification in a nude mouse assay of molecular markers predictive of the capacity of articular cartilage-derived cells (ACDCs) to form ectopic stable cartilage that is resistant to vascular invasion and endochondral ossification. In the present study, we investigated whether in vitro-differentiated mesenchymal stem cells (MSCs) from the synovial membrane (SM) express the stable-chondrocyte markers and form ectopic stable cartilage in vivo. METHODS: Chondrogenesis was induced in micromass culture with the addition of transforming growth factor beta1 (TGFbeta1). After acquisition of the cartilage phenotype, micromasses were implanted subcutaneously into nude mice. Alternatively, cells were released enzymatically and either replated in monolayer or injected intramuscularly into nude mice. Marker analysis was performed by quantitative reverse transcription-polymerase chain reaction. Cell death was detected with TUNEL assay. RESULTS: Cartilage-like micromasses and released cells expressed the stable-chondrocyte markers at levels comparable with those expressed by stable ACDCs. The released cells lost chondrocyte marker expression by 24 hours in monolayer and failed to form cartilage when injected intramuscularly into nude mice. Instead, myogenic differentiation was detected. When intact TGFbeta1-treated micromasses were implanted subcutaneously, they partially lost their cartilage phenotype and underwent cell death and neoangiogenesis within 1 week. At later time points (15-40 days), we retrieved neither cartilage nor bone, and human cells were not detectable. CONCLUSION: The chondrocyte-like phenotype of human SM MSCs, induced in vitro under specific conditions, appears to be unstable and is not sufficient to obtain ectopic formation of stable cartilage in vivo. Studies in animal models of joint surface defect repair are necessary to evaluate the stability of the SM MSC chondrocyte-like phenotype within the joint environment.

Adolescent↗